Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins - PubMed (original) (raw)
doi: 10.1038/ni1047. Epub 2004 Feb 15.
Affiliations
- PMID: 14973438
- DOI: 10.1038/ni1047
Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins
Vigo Heissmeyer et al. Nat Immunol. 2004 Mar.
Abstract
Sustained calcium signaling induces a state of anergy or antigen unresponsiveness in T cells, mediated through calcineurin and the transcription factor NFAT. We show here that Ca(2+)-induced anergy is a multistep program that is implemented at least partly through proteolytic degradation of specific signaling proteins. Calcineurin increased mRNA and protein of the E3 ubiquitin ligases Itch, Cbl-b and GRAIL and induced expression of Tsg101, the ubiquitin-binding component of the ESCRT-1 endosomal sorting complex. Subsequent stimulation or homotypic cell adhesion promoted membrane translocation of Itch and the related protein Nedd4, resulting in degradation of two key signaling proteins, PKC-theta and PLC-gamma1. T cells from Itch- and Cbl-b-deficient mice were resistant to anergy induction. Anergic T cells showed impaired calcium mobilization after TCR triggering and were unable to maintain a mature immunological synapse, instead showing late disorganization of the outer ring containing lymphocyte function-associated antigen 1. Our results define a complex molecular program that links gene transcription induced by calcium and calcineurin to a paradoxical impairment of signal transduction in anergic T cells.
Comment in
- Behind the scenes of anergy: a tale of three E3s.
Davis M, Ben-Neriah Y. Davis M, et al. Nat Immunol. 2004 Mar;5(3):238-40. doi: 10.1038/ni0304-238. Nat Immunol. 2004. PMID: 14985708 No abstract available.
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